1. What is FOXO4-DRI?
FOXO4-DRI (FOXO4-D-Retro-Inverso) is a synthetic peptide designed to selectively interfere with the interaction between the transcription factor FOXO4 and p53. By mimicking a functional region of FOXO4, it has been studied as a potential senolytic agent, aiming to support the clearance of senescent cells while sparing healthy ones. Research into FOXO4-DRI focuses on its role in aging biology, regenerative science, and cell-fate modulation.
2. “DRI”Retro Inverso Peptides Explained
DRI-Retro Inverso Peptides Explained Retro-inverso peptides are linear peptides whose amino acid sequence is reversed and the a-center chirality of the amino acid subunits is inverted as well. Usually, these types of peptides are designed by including D-amino acids in the reverse sequence to help maintain side chain topology similar to that of the original L-amino acid peptide and make them more resistant to proteolytic degradation. Other reported synonyms for these peptides in the scientific literature are:Retro-Inverso Peptides, All-D-Retro Peptides, Retro-Enantio Peptides, Retro-Inverso Analogs, Retro- Inverso Analogues, Retro-Inverso Derivatives, and Retro-Inverso Isomers. D-amino acids represent conformational mirror images of natural L-amino acids occurring in natural proteins present in biological systems. Peptides that contain D-amino acids have advantages over peptides that just contain L-amino acids. In general, these types of peptides are less susceptible to proteolytic degradation and have a longer effective time when used as pharmaceuticals. Furthermore, the insertion of D-amino acids in selected sequence regions as sequence blocks containing only D-amino acids or in-between L- amino acids allows the design of peptide-based drugs that are bioactive and possess increased bioavailability in addition to being resistant to proteolysis. Furthermore, if properly designed, retro-inverso peptides can have binding characteristics similar to L- peptides. Retro-inverso peptides are useful candidates for the study of protein-protein interactions by designing peptidomimetics that mimic the shape of peptide epitopes, protein-protein, or protein-peptide interfases. Retro-inverso-peptides are attractive
alternatives to L-peptides used as pharmaceuticals. These of peptide have been reported to elicit lower immunogenic responses compared to L-peptides.
FOXO4-DRI releases p53 from physiologic sequestration. The p53 protein then targets senescent cells for apoptosis. The net result is an increase in overall tissue fitness and thus improved function at the tissue and
organ level. Improved tissue function is referred to as reduced biological age.
3.FOXO4-DRI Structure
Sequence:H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-G|u-D-lle-D- Ala-D-GIn-D-Ser-D-lle-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-GIn-D-Asn-D-G|y-D-Trp-D-Ala- D-Asn-D-Arg-D-Arg-D-Ser-D-GIy-D-G|y-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D- Arg-D-GIn-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-GIy-OH
Molecular Formula:C₂₂₈H₃₈₈N₈₆O₆₄
Molecular Weight: 5358.05
Synonyms: Forkhead box proteinO4, Proxofim, FOXO4a, AFX, AFX1,MLLT7
4.FOXO4-DRI Research
Mechanism of Interest
l FOXO4-p53 Interaction: FOXO4-DRI competitively binds p53, releasing it from FOXO4 and allowing p53 to initiate programmed cell death in senescence-prone cells【1】.
l Senolytic Specificity: Reported to preferentially affect senescent cells exhibiting the senescence-associated secretory phenotype (SASP).
l Stability: As a retro-inverso peptide, it demonstrates resistance to enzymatic breakdown, prolonging functional presence in experimental systems.
Experimental Observations
l Animal Models: In aged mice, FOXO4-DRI has been studied for effects on fur density, kidney markers, and physical activity (Cell, 2017).
l Progeroid Models: Demonstrated reduction of frailty markers in accelerated aging models.
l Ex Vivo Human Cells: Shown to promote clearance of senescent fibroblasts and reduce inflammatory cytokine levels.
Expert Perspective
Dr. Peter de Keizer, one of the developers, noted: “With FOXO4-DRI, our goal is to target the accumulation of senescent cells, one of the biological hallmarks of aging.”
✅ Why Consider FOXO4-DRI (Research Context)?
l 🧬 Explored for senescent cell targeting in preclinical models
l 🔄 Studied for potential effects on tissue homeostasis and regenerative biology
l 🔒 Non-genotoxic approach compared with traditional chemotherapeutics
l 🔬 Investigated in aging, fibrosis, and cellular stress models
5. Future FOXO4-DRI Research
A. Translation & Delivery
l Human pharmacokinetics and immunogenicity remain under investigation.
l Formulations under exploration include PEGylation and liposomal carriers.
B. Combination Research
l Considered in stacking with Dasatinib + Quercetin, Rapamycin, or NAD+ precursors for broader senolytic strategies.
l Tissue-specific senescence mapping to identify optimal intervention points.
C. Extended Applications
l Fibrosis Models: Investigated in liver, kidney, and pulmonary fibrosis 【2】.
l Neurobiology: Research into senescent glial cells and neuroinflammation.
l Dermatology: Preliminary studies explore topical delivery in skin aging research 【3】.
6. Application Area (Research Use Only)
l 🧪 Senescence biology – mechanisms of cellular aging
l ♻️ Fibrosis & tissue repair research – kidney, liver, and pulmonary models
l 🧠 Neurodegeneration models – senescence-linked glial dysfunction
l 💊 Senolytic development pipelines – testing small molecules & peptide analogs
⚠ Disclaimer
ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.
The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat, or cure any medical condition, ailment, or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.
